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Cholesterol-Interacting Layered Phyllosilicates for Suppressing Gastrointestinal Cholesterol Absorption

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Cholesterol-Interacting Layered Phyllosilicates for Suppressing Gastrointestinal Cholesterol Absorption (19) & (11) EP 2 431 043 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 21.03.2012 Bulletin 2012/12 A61K 33/00 (2006.01) A61K 33/12 (2006.01) A61P 3/06 (2006.01) (21) Application number: 11181650.0 (22) Date of filing: 21.05.2008 (84) Designated Contracting States: • Constantinides, Panayiotis, P. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Gurnee, IL 60031-7565 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: Hiebl, Inge Elisabeth Kraus & Weisert (30) Priority: 23.05.2007 US 966577 P Patent- und Rechtsanwälte 27.02.2008 US 31931 P Thomas-Wimmer-Ring 15 80539 München (DE) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: Remarks: 08780675.8 / 2 167 069 •This application was filed on 16-09-2011 as a divisional application to the application mentioned (71) Applicant: Amcol International Corporation under INID code 62. Hoffman Estates, IL 60192 (US) •Claims filed after the date of filing of the application (Rule 68(4) EPC). (72) Inventors: • Darlington, Jerald, W., Jr. Marengo, IL 60152 (US) (54) Cholesterol-interacting layered phyllosilicates for suppressing gastrointestinal cholesterol absorption (57) Layered phyllosilicates are useful for adsorbing material for use in a method of decreasing the solubility and/or binding to cholesterol and, thereby, reducing of cholesterol in the gastrointestinal tract of a mammalian blood cholesterol in a patient. Accordingly, provided subject. herein is a hydrogen protonated layered phyllosilicate EP 2 431 043 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 431 043 A1 Description Cross-Reference to Related Applications 5 [0001] The present application claims the benefit of priority of U.S. Provisional Application No. 60/966,557, filed May 23, 2007 and of U.S. Provisional Application No. 60/031,931, filed February 27, 2008. The disclosure of each priority application is incorporated herein by reference in their entirety. Field 10 [0002] This invention relates generally to methods and compositions for reducing hypercholesteremia in a mammalian subject. Background 15 [0003] According to recent information from the American Heart Association, an estimated 100,870,000 American adults have total cholesterol levels in the borderline-high risk range of 200 mg/dl to 239 mg/dl. There are 40,600,000 American adults living with high- risk cholesterol levels of 240 mg/dl or more. There are many risk factors that can indicate a propensity to have high levels of cholesterol, such as age, weight, health conditions such as diabetes, smoking, gender, 20 race and ethnicity. Elevated blood cholesterol levels are associated with potentially deadly conditions of the heart and blood vessels, such as atherosclerosis, coronary artery insufficiency and stroke. [0004] Atherosclerosis is the most common cause of death and serious morbidity in the Western world. Atherosclerosis is one of three morphologically distinct forms of arteriosclerosis. Arteriosclerosis is the hardening of the arteries due to their thickening and loss of elasticity. Atherosclerosis occurs when irregularly distributed lipid deposits form in the inner 25 coating of the vessels of the elastic arteries, such as the aorta, carotid and iliac, or the large and medium- sized muscular arteries, such as the coronary and popliteal. These lipid deposits, called atheromatous plaques, cause fibrosis and calcification which leads to coronary heart disease and myocardial infarction. The plaques are comprised of cells, macrophages and other leukocytes, a connective tissue extra-cellular matrix and intracellular and extracellular lipid deposits. The progression of atherosclerosis can be slowed by reducing the plasma cholesterol and cholesterol LDL 30 levels. [0005] Hypercholesterolemia, or elevated blood cholesterol levels due to concentration of cholesterol in the cells and plasma, is also prevalent in the American population. Elevated total and LDL cholesterol levels are considered cardio- vascular risk factors for coronary heart disease and myocardial infarction. [0006] Cholesterol is the most abundant steroid in cell membranes and is essential to the growth and viability of cells. 35 Cholesterol, free and in esterified form, is classified as a lipid and it is a component of lipoproteins, which are complexes of lipids (phospholipids and triglycerides) with proteins. There are four major categories of lipoproteins: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL). Chylomicrons transport some dietary cholesterol and mostly triglycerides from the intestines to the adipose tissue (also known as fat) and-the liver. VLDLs transport cholesterol and triglycerides made by the liver to adipose and other tissues. LDL is a 40 byproduct consisting of apolipoprotein and cholesterol that remains after the fat cells have removed the triglycerides from the VLDL. LDLs transport cholesterol to the peripheral tissues (cells outside the liver and intestine) and regulate the endogenous cholesterol levels therein. LDL is often referred to as the "bad cholesterol" because high levels increase the risk of developing arteriosclerosis and hypercholesterolemia. HDL, known as the "good cholesterol," transports cholesterol from the peripheral tissues (and arterial walls) to the liver. HDLs operate as good cholesterol because they 45 have an opposite function to than of LDLs. It is thought that high levels of HDL can reverse the negative effects of LDL activity. The primary site of cholesterol synthesis is in the liver, although some cholesterol is synthesized in the intestines. The liver’s function in this pathway is to remove the cholesterol from the blood. Plasma LDL is the primary source of cholesterol in peripheral tissues, which do not synthesize cholesterol de novo- LDL is taken into these cells via endocytosis at LDL receptor cites. The molecular genetics and cellular biology of the LDL receptor has been characterized by 50 Goldstein and Brown (Atheroscler Suppl. 2004 Oct;5 (3):57-9). The LDL receptor is essential to cholesterol metabolism. When cholesterol is abundant inside the cell, there is no synthesis of LDL receptors, and thus cholesterol uptake from plasma cholesterol is blocked. The absence of the LDL receptor leads to hypercholesterolemia and atherosclerosis. [0007] Typically, the average person consumes between 350-400 mg of cholesterol daily, while the recommended intake is around 300 milligrams. Increased dietary cholesterol consumption, especially in conjunction with a diet high in 55 saturated fat intake, can result in elevated serum cholesterol. Having an elevated serum cholesterol level is a well- established risk factor for heart disease and therefore there is a need to mitigate the undesired effects of cholesterol accumulation. High cholesterol levels are generally considered to be those total cholesterol levels at 200 milligrams and above or LDL cholesterol levels at 130 milligrams and above. By lowering the total system LDL cholesterol level, it is 2 EP 2 431 043 A1 believed that certain health risks, such as coronary disease and possibly some cancers, that are typically associated with high cholesterol levels, can be reduced by not an insignificant amount. [0008] Numerous studies relating to modifying the intestinal metabolism of lipids illustrate that such effects can reduce a high cholesterol level (Burnett et al., Expert Opin Investig Drugs., 5(11):1337-51, 2006; Wang et al., Am J Physiol 5 Gastrointest Liver Physiol., 287(3):G547-54, 2004; Heidrich et al., BMC Pharmacology, 4:5, 2004; Borel et al., Am. J. Clin. Nutr., 49:1192-1202,1989; Malinow et al., Am. J. Clin., Nutr., 30:2061-2067, 1977). Hampering the absorption of triglycerides, cholesterol or bile acids or a combination of these mechanisms results in a lowering of cholesterol levels in the serum (Lewis et al., Journal of Lipid Research, 36:1098-1105, 1995). [0009] Pharmaceuticals exist to treat elevated cholesterol levels but the majority cause significant side-effects, such 10 as liver problems. For example, patients with hypercholesterolemia are usually started on one of three lipid-lowering therapeutic agents: (1) bile acid-binding resins, (2) niacin; or (3) 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors.These drugs causerespectively: (1) constipation, gastric discomfort, nausea, hemorrhoidal bleeding; (2) arrhythmias, peptic ulcer disease, glucose intolerance, hepatic dysfunction; and (3) abnormal liver function and myositis. If these agents, normally prescribed as the first line of therapy are not successful, fibric acid derivatives like 15 gemfibrozil are often administered. There are also side-effects with this class of drugs, such as lithogenicity of bile, nausea, abnormal liver functions and myositis. [0010] The dietary consumption of clay, including montmorillonite, in animals and humans is known in the art (Carretero, App. Clay Sci., 21:155-163, 2002). There are ancillary reports of montmorillonite being effective as a cholesterol lowering aid. However, although there are limited reports on the adsorption of cholesterol to a layered phyllosilicate materialin 20 vitro (Nikkila et al., Ann. Med. Exp. Biol. Fenn., 30:51-58, 1952), and on a hypocholesterolemic effect of a food-grade silicon dioxide in rats (Peluso et al., J. Nutr., 124:853-860, 1994), there are no specific reports of the effect of layered phyllosilicate materials on intestinal absorption in animals and/or humans. [0011] Of interest
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